Secretory Phospholipase A₂ And Ceramide-induced Programmed Cell Death And Related Signaling Pathways

To study the biologic effects and the underlying mechanism of secretory phospholipase A 2 (sPLA 2) and ceramide, we firstly investigated the relationship between certain lipid signalingmolecules-mediated signal transduction and the sPLA -induced cell death. sPLA is able to induce the intracellular ceramide 2 2 generation followed by programmed cell death. Itwas observed that sphingomyelin plays anegative regulatory role on the activity of sPLA 2, resulting in a strong inhibition on sPLA 2-induced cell death. Conversely, the intracellular sphingomyelinase (SMase) can greatly enhance the cell death inducing effects of sPLA 2. Both sPLA 2 and ceramidehave been shown to inhibit bradykinin-, and PMA-induced phospholipase D activation. These results indicated the existence of a subtle intertwined regulatory interaction between intracellular phosphoglycerol lipids and sphingolipids signaling pathways. In addition, we also found that sPLA can 2 down regulate theepidermal growth factor (EGF)receptor activation. sPLA 2 can significantly inhibits EGF-induced EGF receptorautophosphorylation, which also resulted in the inhibitionon EGF-induced phospholipase D activation and tyrosine phosphorylation of phospholipase C-g 1. Under the same condition, sPLA 2 can induce intracellular ceramidegeneration. Moreover, exogenous ceramide analogs can also significantly inhibit such biologicalevent induced by EGF, suggesting that ceramide may play an important role in sPLA 2-induced cell death and the signaling events. The presented study provided novel experimental evidences for understanding the mechanism of the biological effects of sPLA 2.